1. Field of the Invention
This invention is directed to an antimicrobial material which can be applied to minor wounds, cuts, abrasions and burns for the prevention of infections and for the promotion of rapid healing. More particularly, the invention relates to complexes of polyvinylpyrrolidone (PVP) and iodine. Even more particularly, the invention relates to complexes of crosslinked polyvinylpyrrolidone and iodine capable of providing effective antimicrobial activity while at the same time avoiding wound irritation and retardation of wound healing. The invention also includes a method for preparing such complexes of crosslinked PVP and iodine. The invention further includes preparations, such as powders, gels and the like, which contain such complexes.
2. Description of Prior Art
Current antiseptic products are generally quite effective in reducing microbial counts in vitro, although many of them suffer from limitations inherent in their antimicrobial spectra and are readily inactivated by wound fluid/serum. Another major drawback of currently used antiseptic agents is the relative balance between their antimicrobial efficacy and their cytotoxic potential. When used in concentrations that exhibit adequate antimicrobial activity, they are generally irritating to wounds to varying degrees and/or retard wound healing significantly. Conversely, when used in concentrations which minimize or avoid irritation of wounds or retardation of wound healing, they either do not have sufficient antimicrobial activity in the first instance or their antimicrobial activity quickly dissipates to inadequate levels.
Topical antimicrobial materials and preparations containing them have long been recognized as important parts of disinfection of intact skin and/or wounds. Antimicrobial materials used for this purpose represent a wide variety of chemical compositions including phenols, halogens, peroxides, quaternary ammonium compounds and antibiotics. These antimicrobial agents vary greatly in their effectiveness against different types of micro-organisms to which the skin or wound might be exposed. They also vary greatly in terms of their susceptibility to inactivation by contact with blood, serum or wound fluid as well as changes in pH or ionic environment. Many antimicrobial agents that show a wide effective range of biocidal activity are used for disinfection of inanimate objects such as hard surfaces and instruments but cannot be effectively used on skin or particularly on wounds because of the lack of wide differentiation between their biocidal effects on micro-organisms versus mammalian tissues.
Iodine has long been recognized as an antimicrobial agent with outstanding effectiveness against a wide range of micro-organisms including Gram positive and Gram negative bacteria, mycobacteria, fungi, protozoa and viruses. It remains effective over a wide pH range and, unlike a large majority of other antimicrobial agents, it is not readily inactivated by proteins in the wound fluid/serum. Iodine readily penetrates microbial cell walls and is believed to exert its biocidal activity through a number of interactions including the following:
1) Oxidation of sulfhydryl groups in enzymes and proteins; PA1 2) Inactivation by iodination of phenolic groups in amino acids and proteins; PA1 3) Iodination of basic -NH- groups in amino acids and nucleotides that serve as critical hydrogen bonding sites; PA1 4) Iodination of unsaturated lipids/fatty acids leading to membrane immobilization.
As used in the art, the term "available iodine" refers to any form of iodine that has oxidizing capacity. Such forms are titratable with sodium thiosulfate and include elemental iodine, triiodide ion, hypoiodite ion, and iodate ion.
In a typical aqueous iodine solution, e.g., a solution containing 2% w/v iodine (I.sub.2) and 2.4% w/v sodium iodide (NaI), the available iodine exists in several species in equilibrium with each other. These species include elemental iodine (I.sub.2), hypoiodic acid (HOI), hypoiodite ion (OI.sup..cndot.), hydrated iodine cation (H.sub.2 OI.sup.+), iodate ion [IO.sub.3 ].sup..cndot. and tri-iodide ion [I.sub.3 ].sup..cndot.. Most antiseptic formulations, and the aqueous environment of wounds to which they are applied, have a pH range of 3 to 9. In this pH range of 3 to 9, the concentrations of hydrated iodine cation, hypoiodite ion, and iodate ion are so low that they can be essentially neglected. Tri-iodide ion readily dissociates into elemental iodine and iodide ion in highly diluted solution. Thus, the primary active species in highly diluted aqueous iodine solution are elemental iodine i.e., I.sub.2, and hypoiodic acid, i.e., HOI, in equilibrium. The relative proportions of the two species depends on the pH and the available iodine content. Concentrations of free iodine as low as 0.5 to 2 ppm exhibit antimicrobial effect. The term "free iodine" refers to available iodine which is not bound to another chemical substance such as a polymer or surfactant.
Tincture of iodine, which is a hydro-alcoholic solution of elemental iodine (I.sub.2) and sodium iodide (NaI), is well recognized as a degerming antiseptic and has been in use for presurgical prepping of skin for over one hundred years. However, it is highly irritating, corrosive and toxic when in contact with a body cavity, mucus membranes or wounds. It also has other undesirable side effects that make it unsuitable for wound treatment. These include potential for occasional hypersensitivity reactions, skin staining and unpleasant odor.
Major advances in utilizing the antimicrobial efficacy of iodine while minimizing its tissue toxicity and other undesirable side effects were made with the advent of iodophors. Iodophors are readily dissociable, loose complexes of tri-iodide or iodine with polymers or surfactants. Iodophors not only increase the solubility of iodine in aqueous media but reduce its chemical potential and vapor pressure, thereby reducing its undesirable side effects. The iodophors serve as reservoirs of iodine and function by slowly releasing iodine at the site of application. A well known and very widely used iodophor is polyvinylpyrrolidone-iodine complex, which is also known as PVP-iodine. Since the term "Povidone" is an art recognized synonym for polyvinylpyrrolidone, it will be understood that the term "Povidone-iodine" is synonymous with, and an alternative way of referring to, a polyvinylpyrrolidone-iodine complex. Its available iodine content ranges between 9% and 12%. Spectroscopic studies by Schenck et al., reported in Structure of polyvinylpyrrolidone-iodine, J. Pharm. Sci., 68, p 1505-1509, 1979, indicate that Povidone-iodine consists of adjacent pyrrolidone units complexed with hydrogen tri-iodide rather than elemental iodine. Therefore, only two thirds of its entire iodine content constitutes available iodine. One third of the entire iodine in this complex is in the unavailable iodide form.
Povidone-iodine is utilized in commercially available disinfectant products such as Betadine.RTM. and Isodine.RTM. that are widely used in hospitals for prepping of skin prior to surgery and as surgical scrubs and hand washes for health care personnel hand washes.
Although they are useful for application to intact skin, iodophor solutions as well as most other topically effective antimicrobial preparations based on quaternary ammonium salts or chlorhexidine salts are not well suited for use on wounds. In these preparations, all of the antimicrobially active content is in solution and in direct contact with the wound. Furthermore, in order to be effective over an extended period of time, the concentrations of the active agents far exceed minimum inhibitory concentrations by several orders of magnitude. At these concentrations, the active agents exert cytotoxic, cytopathic or cytostatic effects on the wound tissue as well as on cells, such as fibroblasts, involved in the wound repair process. As a result, the wound repair process is significantly and undesirably retarded.
Lineaweaver et al., Topical antimicrobial toxicity; Arch. Surgery, 120, p 267-270, 1985, found in human fibroblast tissue culture studies that no fibroblasts survived 24 hours after a 15 minute exposure to 1% povidone-iodine, 3% hydrogen peroxide or 0.5% sodium hypochlorite. These studies also showed that the cytotoxicity threshold concentration of soluble povidone-iodine was below 0.01% and above 0.001%. It was also found that re-epithelialization of full thickness dermal wounds on the backs of rats was substantially and statistically significantly inhibited at eight days after initial irrigation with 1% povidone-iodine or with 0.5% sodium hypochlorite.
Rosso, in U.S. Pat. No. 4,323,557, describes adhesives containing N-vinylpyrrolidone in the polymer backbone. In these adhesives, iodine complexing, monomeric units of vinylpyrrolidone are co-polymerized with other adhesive co-monomers. Therefore, the iodine complexing N-vinylpyrrolidone units in this polymeric adhesive are rendered water-insoluble. Pressure sensitive films with such adhesives can be complexed with iodine for providing its slow release. These compositions can be used as antimicrobial surgical drapes. However, they cannot be used on wound surface due to the risk of physical reinjury to the healing wound tissues from direct contact with the adhesive.
Shih, in U.S. Pat. No. 5,242,985, describes a complex of a strongly swellable, moderately crosslinked polyvinylpyrrolidone and iodine. The composition is capable of releasing iodine substantially uniformly over a 6 hour period in the presence of water. Shih's complex is prepared by a method which employs a particular type of crosslinked polyvinylpyrrolidone described in his earlier U.S. Pat. No. 5,073,614. Shih defines narrower ranges for its characteristics (aqueous gel volume, Brookfield viscosity and crosslinker concentration) required for the iodine complex. Shih's iodine complexes are prepared by moistening the specific powdered crosslinked polyvinylpyrrolidone with a small amount of isopropanol or isopropanol/water mixture, mixing the moistened crosslinked polyvinylpyrrolidone with approximately 20%, based on the weight of the PVP polymer of iodine at room temperature, and then heating it at 45.degree. C. for 2 hours and then at 90.degree. c. for 16 hours. The resulting PVP/iodine complex is a light yellow, free flowing fine powder containing approximately 10% available iodine and approximately 5% iodide. The Shih complex releases its available iodine at a uniform rate over a six hour period. In view of this uniform rate of release, the concentration of soluble, available iodine at the wound site will exceed cytotoxic levels within a relatively short period of time, e.g., a few hours, after application of the Shih complex to a wound. This means that use of the Shih material will, at some point in time, undesirably result in wound irritation and/or retardation of wound healing. Those skilled in the art will also notice that nearly one fourth of the iodine used in the preparation of the complex described by Shih et al is unaccounted for and another one fourth is reduced to iodide. This strongly indicates that the starting polymer, i.e., crosslinked polyvinylpyrrolidone, is partially oxidized by iodine during the preparation of the complex under the processing conditions used for iodination. Without wishing to be bound by any particular theory, it is thought that this partial oxidation may account for the observed uniform release pattern of available iodine into the aqueous environment. Although the compositions described in Shih's U.S. Pat. No. 5,242,985 may expose wounds to lower initial iodine levels compared to conventional povidone-iodine, this lower initial level is expected to last for a relatively short time and, as indicated above, cytotoxic levels can be expected to be reached within a few hours.